Background. Recent clinical studies have documented the potential of verapamil for possible increase in coronary blood flow after primary PTCA.

Methods. Forty patients with a first AMI were randomly assigned to the verapamil group (n = 20) or the control group (n = 20). In the verapamil group, verapamil (0.5 mg) was injected into the infarct-related artery shortly after PTCA, followed by the oral administration. We performed MCE with an intracoronary injection of sonicated microbubbles before and after verapamil. To assess microvascular integrity, we determined the baseline-subtracted peak intensity in the risk area and the ratio of the no reflow zone plus the low reflow zone to the risk area (low reflow ratio). We determined the average wall motion score (dyskinesia/akinesia = 3; normal = 0) in the risk area on the day of AMI and a mean of 24 days later.

Conclusions. Intracoronary administration of verapamil after primary PTCA can attenuate microvascular dysfunction and thereby augment myocardial blood flow in patients with AMI, leading to better functional outcome than with PTCA alone.

Coronary reperfusion has been established as an essential therapy for acute myocardial infarction (AMI). Originally, its benefit was considered to be due to timely reestablishment of blood flow to the previously ischemic myocardium. However, we and other investigators have documented [1–6]that myocardial blood flow is occasionally profoundly reduced, even after coronary recanalization, because of microvascular dysfunction in patients with an AMI. This no reflow phenomenon is associated with profound and broad myocardial damage, progressive left ventricular dilation and a high frequency of post-AMI complications [4, 7].

Several studies have attempted to attenuate ischemic microvascular dysfunction with pharmacologic intervention. In a canine study, Stahl et al. [8]demonstrated that postischemic myocardial function can be selectively enhanced by augmentation of blood flow with the intravenous administration of papaverine. In another canine study, Babitt et al. [9]demonstrated that intracoronary administration of adenosine attenuates the progression of microvascular dysfunction after reperfusion. This was associated with an improvement in postischemic myocardial function. In a clinical study, Piana et al. [10]reported that intracoronary verapamil can augment postinterventional coronary blood flow, possibly due to the reversal of microvascular spasm. However, no direct evidence exists as to verapamil’s ability to improve postischemic microvascular function in patients with an AMI or whether such an improvement would lead to a better functional outcome than with coronary reperfusion alone.

In the present study, we performed myocardial contrast echocardiography (MCE) before and after intracoronary injection of verapamil to clarify the direct effect of verapamil on postischemic microvascular function in patients with a reperfused AMI. We then compared functional outcomes in patients with and without verapamil treatment to study the relation between microvascular protection and myocardial salvage.

1 Methods

1.1 Patients

The study included 43 patients who met the following criteria: 1) admission to our hospital with a diagnosis of a first AMI; 2) single-vessel disease; 3) percutaneous transluminal coronary angioplasty (PTCA) of a totally occluded infarct-related artery (Thrombolysis in Myocardial Infarction [TIMI] flow grade 0) within ≤12 h of symptom onset; 4) residual diameter stenosis <50%; 5) no ischemic event during follow-up; and 6) adequate quality of echocardiogram. The diagnosis of AMI was made on the basis of chest pain ≥30 min, AMI-compatible ST segment elevation ≥2 mm on electrocardiographic leads and threefold or greater increase in serum creatine kinase levels. After primary PTCA, we randomly assigned the patients to the verapamil or control group. Three patients were excluded from the study because of severe congestive heart failure at baseline, leaving a final cohort of 40 patients, 20 of whom were assigned to the intracoronary verapamil group and 20 to the control group. Clinical characteristics of the two groups are shown in Table 1. There was no difference in baseline characteristics or prehospital and in-hospital medication between the two groups. The hospital ethics committee approved the study protocol, and written informed consent was obtained from each patient by one of the investigators (Y.T., H.I., K.J., S.T., N.N.).

1.2 Protocol

Patients underwent catheterization by the femoral approach on the day of the AMI. On completion of diagnostic coronary angiography and left ventriculography, 2 ml of sonicated Ioxaglate (Hexabrix-360, Tanabe) containing sonicated microbubbles (mean size 12 μm) was injected into the left main coronary artery for MCE [4, 5]. We initiated imaging of the apical long-axis and parasternal short-axis views ∼10 s before the contrast injection and continued for an average of 30 s with a constant gain setting with a commercially available mechanical sector scanner (model SAL-38B, Toshiba, carrier frequency of 3.5 MHz). We recorded these images on 1.25-cm videotape using a VHS recorder (model BR-6000, Victor). After another contrast injection into the right coronary artery, MCE was repeated. Each patient then underwent primary PTCA. At a mean of 16 min after PTCA, we performed coronary angiography using a 6F diagnostic catheter and recorded the right anterior oblique projection for evaluation of coronary blood flow. We also performed MCE using the same procedure as before, after which 0.5 mg of verapamil, diluted to a total volume of 10 ml with saline, was injected into the infarct-related artery over 1 minute in the verapamil group patients. We then repeated coronary angiography and MCE. In the verapamil group, 120 mg of verapamil was orally administered until the follow-up study.

We performed multiplane two-dimensional echocardiography before PTCA and at a mean of 24 days after the AMI using a commercially available sector scanner (model SSH-65A, SSH-260A, Toshiba, carrier frequency of 3.75 MHz or 2.5 MHz). We recorded echocardiographic images on 1.25-cm VHS videotape. We repeated coronary angiography and left ventriculography at a mean of 25 days after the AMI (24 to 29 days) using the right brachial approach.

1.3 Analysis of Echocardiographic Data

An experienced echocardiographer (Y.T., H.I.) analyzed MCE images with an off-line image analyzing system (Color Cardiology Workstation, TomTec). MCE images were analyzed to identify risk areas and areas of “no reflow,” as described elsewhere [4, 5]. In brief, we defined the areas at risk and no reflow in end-diastolic images as contrast perfusion defects before and after PTCA, respectively. We quantified the area of no reflow as the ratio to the risk area (no reflow ratio). When the ratio exceeded 25%, myocardial reperfusion in the corresponding segment was considered incomplete (MCE no reflow). If this ratio was ≤25%, we considered myocardial reperfusion to be adequate (MCE reflow). We previously demonstrated [4]the high reproducibility of measuring the size of contrast defect. There were myocardial segments that were opacified in a patchy fashion or only in the epicardial layer around the no reflow zone. Ragosta et al. [11]defined such segments as “low reflow” and documented relatively poor functional improvement of these segments. In the present study, we also calculated the ratio of the no reflow area plus the low reflow area to the risk area (low reflow ratio).

Microvascular integrity was assessed with baseline-subtracted contrast intensity in the risk area because contrast intensity is considered to be proportional to myocardial blood volume, which, in turn, is closely related to the density of intact microvascular volume. We previously described [5]our method for determining postintervention contrast intensity in the risk area. Briefly, we identified the initial risk area in the postreflow MCE images by referencing pre-PTCA MCE images. Excluding the endocardial and epicardial borders, we measured contrast peak intensity of the entire myocardial segment of the risk area before and after contrast injection to determine the baseline-subtracted peak intensity (unit/pixel, 256 gray scale; 0 = black; 255 = white).

Left ventricular wall motion was evaluated at baseline and at follow-up, as previously reported [4]. We scored 17 segments of the left ventricle using the following system: 3 = dyskinetic/akinetic; 2 = severely hypokinetic; 1 = hypokinetic; 0 = normal. The wall motion score indexwas defined as the mean score of the segments showing asynergy at baseline. Two independent observers (K.I., S.T.) who had no knowledge of the clinical data determined the segmental score, and a third observer established consensus in cases of disagreement.

1.4 Analysis of Catheterization Data

After mechanical causes of flow reduction, such as critical residual coronary stenosis, apparent dissection, thrombosis or distal vessel cutoff suggestive of macroembolization, were excluded, two radiologists with no knowledge of patient data determined the Thrombolysis in Myocardial Infarction (TIMI) flow grade of the infarct-related artery before and after verapamil [6]. TIMI flow grades have been defined elsewhere [12]. In three cases of disagreement, the final TIMI grade was determined by the consensus of the two radiologists (N.N., Y.H.). Using a cine projector equipped with a frame counter, an angiographer (N.N.) recorded the number of cineframes required from initiation of contrast injection to the opacification of a specified distal landmark (frames to opacification) [10, 13]. These measurements were performed before and after administration of verapamil. An angiographer (N.N.) who had no knowledge of patient data quantified the percent coronary diameter stenosis of the infarct-related artery by the use of a validated technique and analyzed the right anterior oblique projections of baseline and late-stage left ventriculograms to measure left ventricular (LV) end-diastolic volume and LV ejection fraction with the area–length method. Collateral circulation to the infarct-related artery was evaluated according to the classifications of Cohen and Retrop [14].

1.5 Reproducibility of Data

The reproducibility of measuring the contrast intensity was assessed by repeating MCE in five patients. The percent absolute difference between the two trials was 6.3 ± 4.5% (mean ± SD) for the contrast intensity. Intraobserver and interobserver variabilities were determined by measuring the contrast intensity in 10 randomly selected records twice by the same observer and by two independent observers (Y.T., H.I.) who had no knowledge of patient data or the results of the other observer. Intraobserver and interobserver variabilities of peak contrast intensity were 4.2 ± 4.0% and 5.1 ± 4.2% (absolute difference), respectively. The reproducibility of measuring the no reflow zone has been demonstrated elsewhere [4]. We assessed intraobserver and interoberver variabilities of the low reflow ratio using the same patients as before. Intraobserver and interobserver variabilities of peak contrast intensity were 4.7 ± 3.3% and 5.4 ± 3.2% (absolute difference), respectively.

1.6 Statistical Analysis

Results are expressed as mean value ± SD. Multiple comparisons were made by analysis of variance (ANOVA), and individual data were compared by the Scheffé F test for factor analysis. Statistical analysis of temporal changes in certain variables was computed by two-way repeated measures ANOVA and the Scheffé F test. Differences were considered significant at p < 0.05.

2 Results

2.1 Safety of Intracoronary Verapamil

Table 2compares hemodynamic and ECG variables before and after intracoronary injection of verapamil. There was no significant change in any variable before and after verapamil administration. No malignant ventricular arrhythmias, shock or hemodynamic abnormalities were observed during or after intracoronary verapamil.

Myocardial contrast echocardiograms (apical long-axis view) before (right)and after (left)intracoronary administration of verapamil in a patient with AMI. After PTCA, substantial “no reflow” phenomenon showing contrast perfusion defect was observed within the risk area (arrows)during injection of contrast medium into the left main coronary artery before verapamil administration. The size of the no reflow area decreases after verapamil treatment.

Fig. 1demonstrates postinterventional MCE images in a patient with anterior wall acute myocardial infarction before and after intracoronary injection of verapamil. A substantial no reflow zone was observed shortly after PTCA. After intracoronary verapamil, the no reflow zone was substantially reduced.

In the verapamil group, the no or low reflow zone was observed within the risk area after PTCA in 14 patients. Fig. 2illustrates temporal changes in the low reflow ratio in these 14 patients. The low reflow ratio decreased significantly from 0.39 ± 0.23 to 0.29 ± 0.17 after verapamil administration (percent change from before verapamil, 45 ± 32%) (Fig. 2). We then investigated whether the reduction in low reflow ratio is attributable to the reduction in the no reflow zone or low reflow zone, or both. Of the 14 patients, 7 were judged to have MCE no reflow shortly after PTCA. The low reflow ratio significantly reduced after verapamil, even in seven patients with MCE no reflow (0.58 ± 0.17 vs. 0.42 ± 0.14, p < 0.005), but the reduction in the no reflow ratio after verapamil did not reach statistical significance (0.37 ± 0.10 vs. 0.33 ± 0.10, p = NS). Therefore, the reduction in low reflow zone (its ratio to risk area, 0.19 ± 0.14 vs. 0.07 ± 0.09, p < 0.01) may contribute to the reduction in the low reflow ratio of patients with MCE no reflow. Thus, intracoronary verapamil can exert a salutary effect on the preservation of the coronary microvasculature, especially in a low reflow zone that shows patchy enhancement or enhancement only in the epicardial layer. In contrast, MCE revealed good contrast opacification in the risk area after verapamil in the six patients without a no or low reflow zone.⇓

Temporal changes in the low reflow ratio after intracoronary administration of verapamil in 14 patients with no reflow or low reflow zones shortly after PTCA. The low reflow ratio significantly decreased after intracoronary administration of verapamil. Values are expressed as mean ± SD. See text for details.

Temporal changes in baseline-subtracted peak intensity before and after intracoronary verapamil administration in area at risk (ARA) and normal posterior wall (normal). After verapamil, baseline-subtracted peak intensity increased in both areas. The values are lower in the infarct area than in the normal area at both stages. Values are expressed as mean ± SD. ∗p < 0.001 versus area at risk. See text for details.

Fig. 3shows the baseline-subtracted peak intensity in the risk area before and after verapamil in the verapamil group. Baseline-subtracted peak intensity in the infarct region was lower than that in the remote normal region both before and after verapamil (6 ± 5 vs. 27 ± 10, p < 0.001) but increased to 12 ± 6 after verapamil (percent change, 210 ± 152%, p < 0.005 vs. before verapamil).

Coronary angiography revealed that 14 of 20 patients had TIMI grade 3 flow before verapamil, comparable to that in the control group (Table 1). The other six patients (30%) had TIMI grade 2 flow despite the absence of any of residual obstructive lesions. No patient had TIMI grade 0 or 1 patency. After verapamil, the number of patients with TIMI grade 2 reflow decreased to 3, and 17 patients had TIMI grade 3 flow. The number of frames required from the initiation of contrast injection to the opacification of the distal landmark decreased after verapamil (50 ± 15 vs. 41 ± 14, p < 0.01). Changes in these variables in individual patients are summarized in Table 3.

2.3 Functional Outcome

Table 4compares LV functional outcome between the verapamil and control groups. The wall motion score index significantly decreased from baseline to follow-up study in both groups. However, the magnitude of reduction was significantly greater in the verapamil group than in the control group. LV ejection fraction and end-diastolic volume were compared between the two groups. There were no differences in these variables between the two groups at baseline. Significant improvement in LV ejection fraction was observed in both groups, but the degree of improvement was greater in the verapamil group than in the control group. In the verapamil group, LV end-diastolic volume significantly decreased in the convalescent stage, whereas it slightly increased in the control group. Therefore, verapamil treatment seems to restrain LV dilation after primary PTCA.

3 Discussion

Our data demonstrated that intracoronary verapamil after primary PTCA improves microvascular function, leading to better LV functional outcome in patients with AMI than in those treated with PTCA alone. This result implies that there is functionally reversible microvasculature even in the no or low reflow zone, and an increase in myocardial blood flow to the jeopardized myocardium after intracoronary verapamil is associated with better functional outcome than after PTCA alone. Therefore, not only patency of the epicardial coronary artery but also that of the coronary microvasculature could be achieved and maintained with adjunctive pharmacologic treatment to obtain optimal myocardial salvage in patients with AMI.

3.1 Effect of Verapamil on Microvascular Dysfunction

Several clinical studies have demonstrated [1, 3, 6, 10, 15, 16]that sluggish coronary flow, implying angiographic no reflow, is sometimes observed after coronary intervention despite the absence of a flow-restricting epicardial coronary lesion in patients with coronary heart disease. In general, this phenomenon responds promptly to intracoronary verapamil so that microvascular spasm may be reversed. However, to our knowledge, there has been no systematic study of whether intracoronary verapamil actually attenuates microvascular dysfunction in patients with AMI. In the present study, intracoronary verapamil markedly reduced the frequency of TIMI grade 2 flow and the number of cineframes required until opacification of the distal landmark, implying an increase in coronary flow. Our data indicate that the increase in coronary blood flow was associated with a decrease in the size of the no or low reflow zone and an increase in baseline-subtracted peak contrast intensity, indicating attenuation of postischemic microvascular dysfunction. Moreover, this improvement was observed particularly in the low reflow zone, where myocardial perfusion is partially preserved. However, after verapamil there was no significant reduction in the no reflow zone, where myocardial perfusion is very low or nearly absent. Thus, intracoronary verapamil may attenuate microvascular dysfunction, especially in the low reflow zone after PTCA in patients with AMI, and this attenuation may be associated with an increase in coronary blood flow.

Microvascular dysfunction, including the no reflow or low reflow phenomenon, is caused by several factors that increase microvascular impedance, such as neutrophil plugging of the capillaries, myocyte contracture, tissue edema, endothelial blistering and microvascular spasm [17–20]. Several experimental and clinical reports [10, 21]support the contribution of distal microvascular spasm to the microvascular dysfunction. Wilson et al. [22]showed reduced coronary blood flow and transient myocardial ischemia after PTCA only in patients with unstable angina or AMI, which are associated with coronary thrombus. Because angina was not relieved by nitroglycerin or thrombolytic drugs, they considered that profound spasm of the distal microvasculature was probably caused by the release of potent vasoconstrictors from cellular elements (platelet and neutrophil) contained within the thrombus. In a canine experiment, calcium channel antagonists were found to alleviate impairment of endothelium-dependent vasorelaxation caused by transient ischemia [23]. This potent vasodilation of the distal microcirculation may contribute to the favorable response of the no reflow phenomenon to intracoronary verapamil in the present study.

In the present study, the no reflow zone did not totally disappear, and baseline-subtracted peak contrast intensity was still lower in the infarct region than in the normal region even after intracoronary verapamil. Thus, verapamil administration could not totally reverse microvascular dysfunction. Other factors that were not reversed by verapamil administration, such as neutrophil plugging, myocyte contracture, tissue edema and endothelial blistering, could also contribute to the pathogenesis of the no reflow phenomenon. Babbitt et al. [9]suggested that selective administration of adenosine after reperfusion in dogs significantly attenuates functional and structural abnormalities of the previously ischemic microvasculature. They speculated that this beneficial response is caused by attenuation of neutrophil activities with adenosine. Thus, the additional administration of adenosine may further benefit microvascular salvage.

3.2 Effect of Verapamil on Myocardial Salvage

Although the mechanism of verapamil in the salvage of postischemic myocardium is still speculative, several hypotheses have been postulated: 1) Because verapamil works to lower heart rate and arterial pressure, the reduced global oxygen demand may have at least partially contributed to the reduction in infarct size [24, 25]. In fact, reduction of oxygen demand has been shown [26]to reduce infarct size. However, heart rate and blood pressure values were comparable between the verapamil and control groups, even before and after verapamil. 2) Verapamil may inhibit platelet aggregation and possibly thrombus formation in the coronary microvasculature, thereby reducing the obstruction to coronary blood flow and the degree of ischemia [27]. 3) The mechanism is related to its vasodilator effect on the microvasculature. An increase in myocardial blood flow could attenuate the progression of myocardial necrosis and could thereby reduce infarct size [23, 28]. A previous study [8]demonstrated that small-vessel dilation produced by dipyridamole and papaverine administration also enhanced the contractile function of the stunned myocardium. This effect is possibly due to a reduction of the heterogeneity of flow that may exist at the microvascular level. 4) Verapamil may have a direct effect on calcium flux across the sarcolemmal membrane or within intracellular compartments that could have resulted in a protective action on reversibly injured myocytes.

3.3 Study Limitations

The optimal dose of intracoronary verapamil for attenuating microvascular dysfunction remains uncertain. However, we chose the dose on the basis of results of a recent study [10]. The timing of verapamil administration is another issue. We administrated verapamil after identification of the presence or absence of the no reflow phenomenon. Whether verapamil can be adequately delivered to the microvascular bed even after the establishment of the no reflow phenomenon is uncertain. Earlier administration of verapamil might lead to better improvement in the coronary microvasculature and myocardial function.

Semiquantitative and quantitative evaluation of cineangiograms was influenced by several factors, such as oxygen consumption, hemodynamic variables (heart rate and blood pressure), coronary artery size and local autoregulation. The results of MCE should also be considered in the light of several limitations of the analysis. Contrast intensity is influenced by many factors, including the size and number of microbubbles, factors altering ultrasound reflection, such as gain setting, depth of penetration, incident angle, axial and lateral resolution, gray-scale compression and the nonlinearity of echocardiographic amplitude signals.

3.4 Clinical Implications

Success or failure of coronary intervention should be ideally assessed with the recovery of myocardial perfusion. However, the major end point of many angiographic trials has been a patent infarct-related artery. Our results clearly indicate that a patent infarct-related artery does not necessarily guarantee patency of the coronary microvasculature in patients with AMI. Administration of intracoronary verapamil can partially recover microvascular integrity and augment coronary blood flow, resulting in the recovery of good functional outcome. An experimental study [29]has documented a similar salutary effect of diltiazem in attenuating ischemic myocardial injury. Therefore, recanalization of the epicardial coronary artery should not be the only goal. Adjunctive pharmacologic treatment (intracoronary verapamil) can also protect the coronary microvasculature against ischemic injury so that optimal myocardial salvage can be achieved in patients with AMI.

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